Format

Send to

Choose Destination
  • This is a preview / test site. Please update your PubMed URL to pubmed.gov.
See comment in PubMed Commons below
ACS Med Chem Lett. 2017 Sep 5;8(10):1031-1036. doi: 10.1021/acsmedchemlett.7b00223. eCollection 2017.

Synthesis and Pharmacological Evaluation of Selective Histone Deacetylase 6 Inhibitors in Melanoma Models.

Author information

  • 1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  • 2Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC 20052, United States.
  • 3Institute of Biotechnology, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic.
  • 4StarWise Therapeutics LLC, University Research Park, Inc., 510 Charmany Drive, Madison, Wisconsin 53719, United States.

Abstract

Only a handful of therapies offer significant improvement in the overall survival in cases of melanoma, a cancer whose incidence has continued to rise in the past 30 years. In our effort to identify potent and isoform-selective histone deacetylase (HDAC) inhibitors as a therapeutic approach to melanoma, a series of new HDAC6 inhibitors based on the nexturastat A scaffold were prepared. The new analogues 4d, 4e, and 7b bearing added hydrophilic substituents, so as to establish additional hydrogen bonding on the rim of the HDAC6 catalytic pocket, exhibit improved potency against HDAC6 and retain selectivity over HDAC1. Compound 4d exhibits antiproliferative effects on several types of melanoma and lymphoma cells. Further studies indicates that 4d selectively increases acetylated tubulin levels in vitro and elicits an immune response through down-regulating cytokine IL-10. A preliminary in vivo efficacy study indicates that 4d possesses improved capability to inhibit melanoma tumor growth and that this effect is based on the regulation of inflammatory and immune responses.

KEYWORDS:

HDAC6 inhibitors; immune response; inflammatory response; melanoma; nexturastat A

PMID:
29057046
PMCID:
PMC5641951
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00223
[PubMed]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society
    Loading ...
    Support Center